It is becoming increasingly clear that the mechanisms for reproductive aging involve a complex interaction of the three levels of the hypothalamic-pituitary-gonadal (HPG) axis. In rats and other rodents, reproductive cycles become irregular at middle age and acyclicity ensues shortly thereafter, although the ovaries still contain functional follicles. These observations support the role of the hypothalamus and/or pituitary in the transition to acyclicity. My laboratory has been studying a role in reproductive senescence for GnRH neurons, the primary cells controlling reproductive function. Recent evidence suggests that a major mechanism for compromised HPG function during aging is due to age-related alterations in regulatory inputs to GnRH cells. Here, I will investigate the neuroendocrine mechanisms that underlie the transition to acyclicity at middle age, focusing on how the NMDA receptor (NMDAR), which mediates effects of the neurotransmitter glutamate, interacts with GnRH cells at their perikarya in the preoptic area (POA) and neuroterminals in the median eminence (ME), and the consequences of these effects on reproductive decline. My model is young (regular estrous cycles) and middle-aged (regular or irregular cycles, or acyclic) Sprague-Dawley rats; therefore, my analyses will take both age (young vs. middle-aged) and reproductive status (cyclic, irregularly cycling, or acyclic) into consideration as independent variables. Three Specific Aims are proposed to test our hypotheses. Aim 1 will investigate effects of age-related changes in NMDARs in POA, on GnRH cells specifically and in POA nuclei in general. Aim 2 will examine similar relationships in the ME. Aim 3 will study how NMDARs and estrogen receptors (ERs) may be expressed in the same target cells in POA and ME, including GnRH cells, and how these change during reproductive aging. Together, these studies will link GnRH neurons, NMDARs, and ERs, to elucidate how these systems act coordinately to result in the transition to acyclicity at middle age, and to provide insight into their mechanisms. My three Specific Aims form the basis for a model of the perimenopausal transition in women, an area relevant to improving healthy aging, and will provide fundamental and functional insights into the role of the hypothalamus in reproductive senescence. These experiments have clinical implications for postmenopausal hormone replacement therapy, for identifying non- hormonal approaches to treating menopausal symptoms, and for potentially expanding the reproductive lifespan, which is becoming more important as women continue to postpone childbearing until later in life. [unreadable] [unreadable] [unreadable]